The overall goal of the proposed training program is to enhance the applicant's background in pathology and biomedical engineering through acquisition of new knowledge and skill in the areas of experimental cell and molecular biology, and theoretical and experimental cellular biophysics. This new knowledge will help to facilitate the applicant's ultimate career objective as an academic physician: to develop an active research program investigating the role of mechanical phenomena in renal disease. Primary objectives of the research career development plan will include: 1) attainment of comprehensive knowledge and skill in the application of cell and molecular biological techniques to biomedical research questions, and 2) development of specialized knowledge in the area of cell "micro-biomechanics", particularly with respect to the understanding and application of methods used to measure mechanical forces generated by living cells. The proposed research project will facilitate these objectives through an investigation of the role of the podocyte as a structural element within the glomerulus. This function may be undermined in pathologic states associated with glomerular hypertension, resulting in podocyte injury and glomerulosclerosis. The first aim will be to investigate how the force-generating properties of podocytes change when the function of specific myosin protein subtypes is altered using pharmacologic and RNA interference techniques. The second aim will be to develop a transgenic mouse model that fails to express a specific isoform of myosin heavy chain, Myh9, in a podocyte-specific fashion and under temporal control. The third aim will examine the pathophysiologic response of this new mouse model to systemic hypertension. These experiments will help define the structural and mechanical role of the podocyte in maintaining glomerular structure, and will ultimately help identify new approaches to delay progression to end stage renal disease: the permanent loss of kidney function that is common to many kidney diseases, and costly to society. End-stage renal disease is a menace to public health, ultimately costing the American public over $22 billion in treatment costs annually (USRDS 2003 Annual Report), and stealing untold years in productive human life from its citizens. This work will serve as an important step in the effort to reduce the toll of end stage renal disease on the American public.